Uric acid 1,7-dimethyl

Only a few examples have been recorded using ureas as the imidazole nitrogen source. Thus isodialuric acid and urea afforded uric acid when heated in dilute acid and this is one of the earliest recorded preparations of this compound (l889LA(25i)235>. Af-Methyl and N,N-dimethylureas similarly gave low (10%) yields of 7-methyl- and 7,9-dimethyl-uric acid, respectively (25LA(44l)203). 

Fig. 11.1. Separation of some xanthine derivatives Column pBondapak C18 (300x4 rim ID), mobile phase acetonitrile - 0.01 M sodium acetate buffer (pH 4.0) (7 93), flow rate 2.0 ml/min, detection UV 254 nm. Peaks 1, 1-methyluric acid 2, 3-methyl xanthine 3, 1,3-dimethyl-uric acid 4, theobromine 5, theophylline 6, B-hydroxy-ethyltheophylline 7, phenobarbital 8, caffeine 9, 8--chlorotheophyl1ine. (reproduced with permission from ref. 56, by the courtesy of Clinical Chemistry)...

Precolumn Lichrosorb RP2 10 pm (40x2.1 mm ID), column Ultrasphere ODS 5 pm (250x4.6 mm ID), mobile phase gradient with solvent A 0.01 M sodium acetate and 0.005 M tetrabutylammonium hydrogen sulfate in water (pH 4.9), solvent B same salt concentrations in 50% methanol (pH 4.8). Gradient 0-7.5 min 0 B, 7.5-15 min 0-T5% B, 15-25 min 15-30% B, 25-33 min 30-32% B, 33-38 min 32-45% B and 38-41 min 45-0% 6. Detection UV 280 nm. Peaks 1, xanthine 2, uric acid 3, 3-methyluric acid 4, 7-methyl xanthine 5, 3-methyl xanthine 6, 1-methylxanthine 7, theobromine 8, 3,7-dimethyl uric acid 9, 7-methyluric acid 10, 1-methyluric acid 11, 1,3-dimethyluric acid 12, 1,7-dimethyl xanthine 13, theophylline 14, e-hydroxyethyltheophylline (internal standard) 15, 1,7-dimethyluric acid 16, 1,3,7-trimethyluric acid 17, caffeine, (reproduced with permission from ref. 192, by the courtesy of Journal Chromatographic Science)... 

Theophylline 1,3-Dimethyl uric acid Cardiotoxicity has been demonstrated... 

Chemically, theophylline is 1,3-dimethylxanthine and contains both an acidic and a basic nitrogen (N-7 and N-9, respectively). Physiologically, it behaves as an acid (pKa = 8.6), and its poor aqueous solubility can be enhanced by salt formation with organic bases. Theophylline is metabolized by a combination of C-8 oxidation and N-demethylation to yield methyluric acid metabolites (Fig. 44.20). The major urinary metabolite is 1,3-dimethyl uric acid, which is the product of the action of xanthine oxidase. Beoause none of the metabolites is uric acid itself. 

Methyl uric acid 3-Methyl uric acid 7-Methyl uric acid 9-Methyl uric acid 1,3-Dimethyl uric acid... 

Methyluric acids are common decomposition products of methylxanthines such as caffeine. Five such compounds (I- and 7-melhyluric acid, 1,7- and 13-dimethyl-uric acid, and 1,3,7-trimethyluric acid) were extracted from urine and sqjarated on a Cj column (A = 280nm). A two-ramp 95/5— 80/20 (at 8 min)- 70/30 (at 15 min) water (acetate pH 3.5)/methanol gradient generated excellent separation and peak shapes [375]. The linear range was 25 pg/mL to 3 mg/mL with reported detection limits of lOng/mL. 

In addition to the intramolecular effects, steric factors are of considerable influence. The most usual one consists of steric hindrance to attack on the lactam nitrogen atom. Certain examples of this will be given. By comparison with uracil, it would be expected that uric acid (10) would be iV-methylated in the pyrimidine ring, but that in the imidazole ring 0-methylation should also be possible. However, the experiments of Biltz and Max show that all uric acid derivatives which carry a hydrogen atom in the 9-position are converted by ethereal diazomethane into l,3,7-trimethyl-8-methoxyxanthine (11). The following are examples uric acid and its 1-methyl, 3-methyl, 7-methyl, 1,3-dimethyl, 1,7-dimethyI, 3,7-dimethyl, and 1,3,7-trimethyl derivatives. Uric acid derivatives which arc substituted by alkyl groups in the 3- and 9-positions (e.g., 3,9-dimethyl-, 1,3,9-trimethyl-, and 3,7,9-trimethyl-uric acid)do not react at all with diazomethane, possibly because of insufficient acidity. Uric acids which are alkylated... 

HPLC coupled to MS was used for the determination of dimethyl xanthine metabolites in plasma.82 There have also been a number of methods published on the use of HPLC with a PDA detector. In 1996, Mei published a method for the determination of adenosine, inosine, hypoxanthine, xanthine, and uric acid in microdialysis samples using microbore column HPLC with a PDA detector.63 In this method, samples were directly injected onto the HPLC without the need for any additional sample treatment. 

Fig. 11) would likely proceed by different mechanisms. Protonation of the diol (IV, Fig. 12) derived from theobromine would lead to ring opening at the C6— Cs position giving an imidazole isocyanate (XVI, Fig. 12). This could readily form XVII which after hydrolysis and loss of C02 would give dimethyl-allantoin (XVIII). On the other hand, the uric acid diol derived from caffeine (X, Fig. 12) cannot fragment by this mechanism. Accordingly, either or both of the processes could Occur via the form of the diol hydrated at the C6 carbonyl group (XIX, Fig. 12) which could readily lose C02 to give XX followed by rearrangement to trimethylallantoin (XXI).

HTAC and HTAH have been used as surfactants in the chemiluminescence reaction of lucigenin (10,10 -dimethyl-9,9 -biacridinium dinitrate) with biological reductants (such as fructose, glucose, ascorbic and uric acid) or hydrogen peroxide [38],... 

Further investigation on the chemistry of the very potent diuretic drug ethacrinic acid W led to a compound that retained the high potency of the parent with reduced propensity for causing side effects, such as loss of body potassium and retention of uric acid. Friedel-Crafts acylation of dichioroanisole with phenyl acetyl chloride gives ketone 10. This is then reacted in a variant of the Mannich reaction which involves the aminal from dimethyl-... 

Tetramethyluric acids 200, 201 and 202 14C-labelled at C(2) have been synthesized203 by methylation of [2-14C]uric acid (specific activity SlmCimmol-1) with dimethyl sulphate at pH 9 (during 22 h), in 44.9%, 4.4% and 6.3% yields, respectively, in order to study their mode of action on the genetic material204 and to elucidate their metabolic fate in caffeine-containing plants205 206 or in mammals. 

The naturally occurring purines fall into 4 main groups. (1) Simple substituted derivatives of purine (1) such as adenine (2) and various 6-AT-substituted derivatives. (2) Monoxo-dihydropurines such as hypoxanthine (3), guanine (4), and isoguanine (5). f3) Dioxotetra-hydropurines such as xanthine (6) and methylated derivatives including the 3,7-dimethyl derivative theobromine (7), 1,3-dimethylxanthine or theophylline f8), and 1,3,7-trimethylxanthine or caffeine (9). (4) Trioxohexahydropurines such as uric acid (10). 

Alkylation of the triethylsilylated uric acid (120) with methyl iodide is unusual in produdng 1-methyluric acid but at 150 °C with dimethyl sulfate the major products isolated were... 

The highest susceptibility to oxidation with chlorine is found in trioxopurines therefore, the major studies have been carried out with uric acid derivatives. Some contributions from xanthine chemistry have also been made. Chlorination of theobromine (1) in aqueous solution gives 4,5-dihydroxy-3,7-dimethyl-4,5-dihydrouric acid (2) while chlorination in dilute acetic acid affords 5-chloro-3,7-dimethylisouric acid (3). ° " ... 

The examples provided above indicate that single enantiomers are not always better alternatives to their respective racemates. Another interesting example is 5-dimethyl-sulphamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxilic acid, a racemic diuretic whose diuretic activity is attributed to the S(—)-enantiomer, while theR(+)-enantiomer has uricosuric properties that suppress the S-enantiomer-induced side-effect of elevated blood uric acid (21). It is not known if marripulation of the S R ratio of this drug, as is seen for indocrinone (below), results in a better diuretic agent. 

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